The rockefeller university

Event Details

Type

Friday Lecture Series

Speaker(s)

Louis M. Staudt, M.D., Ph.D., director, center for cancer genomics and co-chief, lymphoid malignancies branch and head, molecular biology of lymphoid malignancies section, Center for Cancer Research, National Cancer Institute at the National Institutes of Health

Speaker bio(s)

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous diagnostic category that is comprised of two prominent molecular subtypes, termed activated B cell-like (ABC) and germinal center B cell-like (GCB). These DLBCL subtypes are now viewed as molecularly distinct diseases since they arise from distinct stages of normal B cell development, require distinct recurrent genetic abnormalities to become malignant, have distinct cure rates with current chemotherapy regimens, and respond differentially to targeting agents. Dr. Staudt's group has defined a “chronic active” form of B cell receptor (BCR) signaling that activates NF-kB in ABC DLBCLs. Such ABC DLBCLs are killed by knockdown of BCR signaling components, such as the kinase BTK or components of the BCR itself. Over one-fifth of ABC DLBCLs have mutations affecting the CD79B or CD79A subunits of the BCR that augment BCR signaling. To attack chronic active BCR signaling therapeutically, Dr. Staudt's group initiated clinical trials in relapsed/refractory DLBCL of ibrutinib, an irreversible and highly selective inhibitor of BTK. Ibrutinib monotherapy induced a high rate of complete and partial responses in ABC DLBCL, while GCB DLBCL tumors rarely responded. Genetic analysis of responding tumors demonstrated an enrichment for those with CD79B mutations, but most responses were observed in tumors with wild type BCR subunits. This observation allowed Dr. Staudt to define a non-genetic mechanism of BCR activation that depends on reactivity of the lymphoma BCR to self antigens. To extend the efficacy of ibrutinib, they have identified additional therapeutic targets in the BCR signaling pathway, including ubiquitin ligases such as LUBAC. They have also defined other oncogenic signaling pathways in ABC DLBCL that cooperate with BCR signaling to sustain cell survival, including the MyD88 pathway, which is activated by oncogenic MYD88 mutations in approximately 40 percent of cases. Several synergistic, mechanism-based drug combinations that exploit these redundant survival pathways will be presented.

 

Dr. Staudt received his M.D. and Ph.D. degrees in 1982 from the University of Pennsylvania. His Ph.D. thesis revealed somatic hypermutation as a mechanism of rapid antibody diversification during normal immune responses. Following Internal Medicine training, he joined David Baltimore's laboratory at the Whitehead Institute where he cloned and characterized the first tissue specific transcription factor, Oct-2. In 1988, he established his laboratory at the National Cancer Institute (NCI), which now focuses on the molecular basis for human lymphoid malignancies and the development of targeted therapies for these cancers. Dr. Staudt has received numerous awards for his research, including the 2009 Dameshek Prize from the American Society of Hematology for outstanding contribution in hematology and election to the National Academy of Sciences in 2013.

Open to

Public

Reception

Refreshments, 3:15 p.m. - 3:45 p.m., Abby Lounge

Contact

Linda Hanssler

Phone

(212) 327-7714

Sponsor

Linda Hanssler
(212) 327-7714
lhanssler@rockefeller.edu

Readings

http://librarynews.rockefeller.edu/?p=3652